【摘 要】
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Human dihydroorotate dehydrogenase(DHODH)is a viable target for the development of therapeutics to treat cancer and immunological diseases,such as rheumatoid ar
【机 构】
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Shanghai Key Laboratory of Chemical Biology,School of Pharmacy,East China University of Science&Tech
论文部分内容阅读
Human dihydroorotate dehydrogenase(DHODH)is a viable target for the development of therapeutics to treat cancer and immunological diseases,such as rheumatoid arthritis(RA),psoriasis and multiple sclerosis(MS).Herein,a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents were designed and synthesized.2-Acrylamidobenzoic acid analog 11 was identified as the lead compound for structure-activity relationship(SAR)studies.The replacement of the phenyl group with naphthyl moieties improved inhibitory activity significantly to double-digit nanomolar range.Further structure optimization revealed that an acrylamide with small hydrophobic groups(Me,Cl or Br)at the 2-position was preferred.Moreover,adding a fluoro atom at the 5-position of the benzoic acid enhanced the potency.The optimization efforts led to potent compounds 42 and 53-55 with IC50 values of 41,44,32,and 42 nmol/L,respectively.The most potent compound 54 also displayed favorable phar-macokinetic(PK)profiles and encouraging in vivo anti-arthritic effects in a dose-dependent manner.
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